CERTAIN 6,11-DIHYDRO-11-(3-ALPHA-TROPANYLOXY)-DIBENZO[b,e]THIEPINE-5-OXIDES AND THE CORRESPONDING DIOXIDES AND DERIVATIVES THEREOF

ABSTRACT

WHEREIN R is alkyl of one to four carbon atoms and n is 1 or 2, or R is alkyl of two to four carbon atoms and n is 0, AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF. The compounds are useful in the prophylaxis and treatment of gastric ulcers.   The invention concerns new dibenzothiepines of the formula:

United States Patent [191 Gadient CERTAIN 6,1 l-DlHYDRO-l I-(S-ALPHA- TROPANYLOXY)-DIBENZO[B,E] THIEPINE-S-OXIDES AND THE CORRESPONDING DIOXIDES AND DERIVATIVES THEREOF [75] Inventor: Fulvio Gadient, Birsfelden, Switzerland [73] Assignee: Sandoz Ltd., Basle, Switzerland [22] Filed: July 13, 1971 [21] Appl. No.: 162,290

[30] Foreign Application Priority Data July 15, 1970 Switzerland ..10735/70 July 15, 1970 Switzerland ..lO736/70 July 15, 1970 Switzerland ..l0737/70 July 15, I970 Switzerland ..l0738/70 [52] US. Cl ..260/292, 260/327 R, 424/265 [5 l Int. Cl. ..C07d 43/06 [58] Field of Search ..260/292, 327 B, 327 R [5 6] References Cited UNITED STATES PATENTS 3,234,235 2/1966 Davis et al. ..260/327 B 3,413,296 ll/l968 Jucker et al ..260/292 Feb. 13, 1973 Primary Examiner--Alan L. Rotman Att0rneyGerald D. Sharkin et al.

[57] ABSTRACT The invention concerns new dibenzothiepines of the wherein R is alkyl of one to four carbon atoms and n is l or 2, or

R is alkyl of two to four carbon atoms and n is 0, and pharmaceutically acceptable acid addition salts thereof. The compounds are useful in the prophylaxis and treatment of gastric ulcers.

5 Claims, No Drawings IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS This invention relates to dibenzothiepine derivatives. In accordance with the invention there are provided new dibenzothiepines of formula I,

wherein R is alkyl of one to four carbon atoms and n is I or 2, or R is alkyl of two to four carbon atoms and n is 0,

and acid addition salts thereof.

Further, in accordance with the invention a compound of formula I is obtained by a process comprising a. reacting a compound of formula III,

wherein R is alkyl ofone to four carbon atoms, with a compound of formula II,

wherein n is 1 or 2, or, when R in the compound of formula III is alkyl of two to four carbon atoms, n is 0, and X is the acid radical of a reactive ester, in the presence of an inert organic solvent, or b. reacting a compound of formula Ia,

wherein R' is alkyl oftwo to four carbon atoms, in neutral or weakly acid solution, with an alkali metal Salt or alkaline earth metal salt of periodic acid, or with the stoichiometric amount of an organic peracid or with the stoichiometric amount of hydrogen peroxide, to obtain a compound of formula lb,

wherein R is alkyl of one to four carbon atoms, 0. oxidizing a compound of formula la or lb in acid solution with hydrogen peroxide or an organic peracid to a compound of formula Ic,

wherein R is alkyl of one to four carbon atoms, and, where an acid addition salt is required, converting the resulting compound of formula I into such salt.

In the claims, the dibenzothiepines of formula I have been defined by the formulae:

O l) Y Y A wherein m is 1 or 2,

R is alkyl of one to four carbon atoms, and R is alkyl of two to four carbon atoms.

Process variant (a) may, for example, be effected as follows: A solution of a compound of formula II, wherein X is preferably chlorine, bromine, iodine or fluorine, or the radical of an organic sulphonic acid, in an inert solvent, e.g., an aromatic hydrocarbon such as absolute toluene or absolute benzene, is added dropwise at an elevated temperature, conveniently under reflux at the boiling temperature of the reaction mixture, optionally in the presence of an acid-binding agent, e.g., an alkali metal carbonate such as sodium or potassium carbonate, or a tertiary organic base such as triethylamine, to a solution of a nortropine or pseudonortropine alkyl derivative (nortropan-3a-ol or nortropan-3B-ol derivatives) in the same solvent.

Process variant (b) is preferably effected at a low temperature, preferably between and 50 C, and optionally in an inert solvent, e.g., acetic acid or acetone. Reaction times under preferred conditions are of the order of to hours.

Process variant (c) is preferably effected using an excess of hydrogen peroxide or an organic peracid. An inert solvent, e.g., glacial acetic acid or acetone, is preferably used. The reaction is suitably carried out at an elevated temperature, preferably at a temperature between about 50 and l50 C, and may have a duration of about 3 to l0 hours under preferred conditions.

The resulting compounds of formula I may be worked up and optionally purified in accordance with known methods.

In the process of the invention the steric configuration remains unchanged, so that, e.g., when nortropan- Sa-ol derivatives are used in accordance with embodiment (a) of the process, the corresponding ll-(8-alkyl- 3a-nortropanyloxy)-6,l l-dihydrodibenzo-{ b,e]thiepine derivatives are obtained, and this configuration is also maintained in the case of an oxidation in accordance with process variants (b) and (c).

The preferred compounds of formula ll may be obtained as follows:

a. a compound of formula lla,

wherein n is O, l or 2, and

X is the radical of an organic sulphonic acid, is

produced by reacting a compound of formula IV,

wherein n is 0, l or 2, with an organic sulphonic acid halide in an inert solvent, or b. a compound offormula llb,

is produced by passing hydrogen chloride, bromide or iodide through a solution of a compound of formula IV ill;

in an inert solvent, or c. a compound of formula He,

wherein n is 0, l or 2, is produced by reacting a compound of formula lld,

@rk Y X 1rd wherein n is 0, 1 or 2, and

X' is chlorine or bromine, with a metal fluoride, or d. a compound of formula llb is produced by reacting a compound of formula IV with thionyl chloride or bromide, or phosphorus chloride, bromide or iodide.

Process (a) is preferably carried out in a basic medium and an organic basic solvent, e.g., pyridine, or a lower trialkylamine such as triethylamine, is preferably used as inert solvent, or the reaction is effected in an inert organic solvent with the addition of pyridine or a lower trialkylamine.

An anhydrous aromatic hydrocarbon such as benzene may, for example, be used as solvent in process (b). The ll-iodo derivative may likewise be produced from the l l-bromo derivative by reaction with sodium iodide in acetone.

In process (d) phosphorus trichloride, tribromide or pentachloride may, for example, be used as phosphorus halide.

A compound of formula He,

wherein X is as defined above, may likewise be obtained by reacting a compound of formula llf,

;:F XK

wherein X is as defined above, in neutral or weakly acid solution, with an alkali or alkaline earth salt of periodic acid, or with the stoichiometric amount of an organic peracid or with the stoichiometric amount of hydrogen peroxide, in a manner analogous to process variant (b) for the production of compounds of formula lb.

A compound of formula Hg,

wherein X is as defined above, may be obtained by oxidizing a compound of formula He or llfin acid solution with hydrogen peroxide or an organic peracid, in a manner analogous to embodiment (c) of the process for the production of compounds of formula lc.

A compound of formula la may be obtained by reacting a compound of formula llfwith a compound of formula III in accordance with process variant (a).

Insofar as the production of the starting materials is not particularly described, these are known or may be produced in accordance with known processes or in a manner analogous to the processes described herein or to known processes.

The compounds of formula I and pharmaceutically acceptable acid addition salts thereof are useful because they possess pharmacological activity in animals. In particular, the compounds are useful in the prophylaxis and treatment of gastric ulcers as indicated by the anticholinergic and histaminolytic tests in guinea pigs, the mydriasis test in mice, and further by an inhibition of phenylbutazone-induced ulcer formation in rats.

For the above mentioned use, the dosage administered will, of course, vary depending upon the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 0.05 to about mg per kilogram animal body weight, conveniently given in divided doses 2 to 3 times a day, or in sustained release form. For the larger mammals, the total daily dosage is in the range of from about 2 to 10 mg, and dosage forms suitable for oral administration comprise from about 0.6 to about 5 mg of the compound, in association with a solid or liquid pharmaceutical carrier or diluent.

The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salts possess the same order of activity as the free bases and are readily prepared in conventional manner. Suitable such salt forms include mineral acid salts such as the hydrochloride, hydrobromide and sulphate, and organic acid salts such as the fumarate, maleate, tartrate, methane ethaneand benzene-sulphonate, citrate and malate.

The invention also provides a pharmaceutical composition comprising as active agent a compound of formula l, or pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier or diluent.

In the following nonlimitative Examples all temperatures are indicated in degrees centigrade and are uncorrected.

EXAMPLE 1 l l-(8-Ethyl-3u-nortropanyloxy)-6,l l-dihydrodibenzo [b,e]thiepine [process variant (a)] Hydrogen chloride is passed through 22.7 g of 6,1 ldihydrodibenzo[b,e]thiepin-l l-ol in 50 cc of absolute benzene for 15 minutes while cooling with ice. The solution is subsequently concentrated completely, the residue is dissolved in 50 cc of absolute benzene, is dried over magnesium sulphate and again concentrated completely. The crude l l-chloro-6,l ldihydrodibenzo-[b,e]thiepine is then dissolved in cc of absolute xylene, and this solution is added dropwise to a boiling solution of I55 g of N-ethyl-nortropine in 50 cc of absolute xylene over a period of IS minutes. The reaction mixture is then heated to the boil under reflux for 1 hour, is cooled to room temperature, diluted with lOO cc of diethyl ether and extracted twice with 50 cc amounts of 2 N hydrochloric acid. The aqueous extract is rendered alkaline with 2 N caustic soda solution, is extracted thrice with cc amounts of ether, the combined ether extracts are dried over magnesium sulphate, purified with animal charcoal, and the solvent is completely distilled off. The oily residue, i.e., the title compound, is converted into the methanesulphonate, which has an M.P. of 198-200 after recrystallization from ethanol.

EXAMPLE 2 6,1 l-Dihydro-l l-( 8-n-propyl-3a-nortropanyloxy)- dibenzo[b,e]thiepine 6,l l-Dihydrodibenzo[b,e]thiepin-l 1-0] is reacted with hydrogen chloride to obtain 1 l-chloro-6,l ldihydrodibenzo[b,e]-thiepine and this is subsequently reacted with N-n-propyl-nortropine in accordance with the process described in Example 1. The hydrogen fumarate of the title compound has an M.P. of 203-205 EXAMPLE 3 6,l l-Dihydro-l l-(8-isopropyl-3a-nortropanyloxy)- dibenzo[b,e]thiepine 6,ll-Dihydrodibenzo[b,e]thiepin-ll-ol is reacted with hydrogen chloride to obtain 1l-chloro-6,lldihydrodibenzo[b,e]-thiepine and this is subsequently .reacted with N-isopropyl-nortropine in accordance with the process described in Example 1. The title compound has an M.P. of l26-l 27.

EXAMPLE 4 l l-(8-n-Butyl-3a-nortropanyloxy)-6,l ldihydrodibenzo[b,e]thiepine 6,ll-Dihydrodibenzo[b,e]thiepin-ll-ol is reacted with hydrogen chloride to obtain ll-chloro-6,lldihydrodibenzo[b,e]-thiepine and this is subsequently reacted with N-n-butyl-nortropine in accordance with" the process described in Example 1. The hydrogen fumarate of the title compound has an M.P. of 230 (decomp.).

EXAMPLE 5 dropwise to a boiling solution of 14.1 g of tropine (tropan-3a-ol) in 50 cc of absolute xylene over a period of 15 minutes. The reaction mixture is subsequently heated to the boil under reflux for 1 hour, is then cooled to room temperature, diluted with 100 cc of diethyl ether and extracted twice with 50 cc amounts of 2 N hydrochloric acid. The aqueous extract is then rendered alkaline with 2 N caustic soda solution, is extracted thrice with 100 cc amounts of ether, the combined ether extracts are dried over magnesium sulphate, purified with animal charcoal, and the solvent is completely distilled off. The oily residue, i.e., the title compound, is converted into the hydrogen fumarate, which has an MP. of l25-l27 after recrystallization from methanol.

The starting material is obtained as follows:

2.8 cc of a 40 percent hydrogen peroxide solution are added to a solution of 7.2 g of 6,l ldihydrodibenzo[b,e]thiepin-l l-ol in 45 cc of glacial acetic acid, and the mixture is stirred at room temperature for 17 hours. The reaction solution is subsequently diluted with 70 cc of water, is cooled and rendered alkaline with a 25 percent ammonia solution. The aqueous phase is extracted thrice with l cc amounts of ether, the combined ether extracts are dried over magnesium sulphate and the solvent is completely evaporated at reduced pressure. The residue is used for the next reaction without further purification.

EXAMPLE 6 6,1 l-Dihydro-l l-(3a-tropanyloxy )-dibenzo[b ,e lthiepine-S ,5 -dioxide [process variant (a)] 7.3 g of thionyl chloride are added to 15.8 g of 6,1 ldihydro-l l-hydroxy-dibenzo[b,e]thiepine-5,5-dioxide in 40 cc of absolute xylene, and the mixture is heated to 70 for l hour. After cooling to room temperature, 3.0 g of calcium chloride are added and the xylene phase is filtered in the absence of moisture. The xylene phase is subsequently added dropwise within minutes to a boiling mixture of 8.6 g of tropine and 24.6 g of sodium carbonate in 50 cc of absolute xylene. The reaction mixture is heated under reflux for 6 hours and after cooling, is diluted with 200 cc of diethyl ether and extracted twice with 100 cc amounts of water. The organic phase is extracted with 100 cc of N hydrochloric acid, the hydrochloric acid extract is rendered. alkaline with 2 N caustic soda solution and is extracted thrice with 300 cc amounts of diethyl ether. After drying the ether extract over sodium sulphate, the solvent is distilled off at reduced pressure. The oily residue, i.e.,, the title compound, is then converted into the methanesulphonate with methanesulphonic acid in methanol; after recrystallization from methanol the methanesulphonate of the title compound has an M.P. of 225-230.

EXAMPLE 7 6,1 l-Dihydro-l l-( 3a-tropanyloxy)-dibenzo[b,e lthiepine-S -oxide [process variant (b)] 2.8 cc of a 40 percent hydrogen peroxide solution are added to a solution of 10.5 g of 6,1 l-dihydro-l l(3 a-tropanyloxy)dibenzo'-[ b,e]thiepine in 45 cc of glacial acetic acid, and the mixture is stirred at room temperature for 17 hours. The reaction solution is subsequently diluted with 70 cc of water, is cooled and rendered alkaline with a 25 percent ammonia solution. The aqueous phase is extracted thrice with 100 cc amounts of ether, the combined ether extracts are dried over magnesium sulphate and the solvent is completely concentrated at reduced pressure. The oily residue, i.e., the title compound, is then converted into the hydrogen fumarate with fumaric acid in ethanol. After recrystallization from methanol the hydrogen fumarate ofthe title compound has an M.P. of l25-l 27.

The 6,l l-dihydro-l l-(3a-tropanyloxy)dibenzo[b,e] thiepine, required as starting material, may be produced as follows:

7.3 g of thionyl chloride are added to 14.0 g of 6,1 ldihydrodibenzo[b,e]thiepiri 1l ol in 40 cc of absolute xylene, and the mixture is heated to for 1 hour. After cooling to room temperature, 3.0 g of calcium chloride are added and the xylene phase is filtered in the absence of moisture. The xylene phase is subsequently added dropwise within l5 minutes to a boiling mixture of 8.6 g of tropine (tropan-Ba-ol) and 24.6 g of sodium carbonate in 50 cc of absolute xylene. The reaction mixture is heated under reflux for 6 hours and after cooling, is diluted with 200 cc of diethyl ether and extracted twice with 100 cc amounts of water. The organic phase is extracted with 100 cc of N hydrochloric acid, the hydrochloric acid extract is rendered alkaline with 2 N caustic soda solution and is extracted thrice with 300 cc amounts of diethyl ether. The ether extract is dried over sodium sulphate, is subsequently concentrated and the oily residue is distilled, whereby the title compound distills over at l90-2(l0 and 0.02 mm of Hg.

EXAMPLE 8 l l-(8-Ethyl-3rx-nortropanyloxy)-6,l l-dihydrodibenzo [b,e]thiepine-5-oxide The title compound is obtained in accordance with the process described in Example 7 (c)]l l-(8-ethyl-3anortropanyloxy)-6,l l-dihydrodibenzo[b,e]thiepine. The hydrogen fumarate of the title compound has an MP. of 134 (Dec) EXAMPLE 9 6,1 l'DihydroJ l-(3a-tropanyloxy)-dibenzo[b,e ]thiepine-5,5-dioxide [process variant (c)] 5.6 cc of a 40 percent hydrogen peroxide solution are added to a solution of l0.5 g of 6,1 l-dihydro-l l-(3 a-tropanyloxy )dibenzo-[b,e]thiepine in 45 cc of glacial acetic acid, and the mixture is heated in an oil bath of for 7 hours. After cooling to room temperature, the mixture is diluted with 70 cc of water and the solution is rendered alkaline with a 25 percent ammonia solution while cooling. The aqueous phase is then extracted thrice with 200 cc amounts of chloroform, the combined chloroform phases are dried over magnesium sulphate and the solvent is distilled off at reduced pressure. The oily residue, i.e., the title compound, is then converted into the methanesulphonate with methanesulphonic acid in methanol. After recrystallization from methanol, the methanesulphonate of the title compound has an MP. of 225230.

EXAMPLE l0 1 l-(8-Ethyl-3a-nortropanyloxy)6,l l-dihydrodibenzo [b,e]thiepine-5,5-dioxide The title compound is obtained by treating 11-(8- ethyl-3a-nortropanyloxy)-6,I 1-dihydrodibenzo[ b,e]thiepine with hydrogen peroxide in accordance with the process described in Example 9. The hydrogen fumarate of the title compound has an M.P. of 157159 (decomp.).

EXAMPLE 1 1 6,1 l-Dihydro-l 1-(3a-tropanyloxy)-dibenzo[b,e] thiepine-5,5-dioxide The title compound is obtained by treating 6,11- dihydro-l 1-(3a-tropanyloxy)dibenzo[b,e]thiepine-5- oxide with hydrogen peroxide in accordance with the process described in Example 9. The methanesulphonate of the title compound has an M.P. of 225-230.

EXAMPLE 12 wherein R is alkyl of one to four carbon atoms, and

m is 1 or 2, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1, which is 6,11-dihydro- 11-(3a-tropanyloxy dibenzo[b,elthiepine-S-oxide.

3. The compoun of claim 1, which is 6,1 l-dihydro- 1 1-(3a-tropanyloxy )dibenzo[b,e]thiepine-S,S-dioxide. 4. The compound of claim 1, which is l 1-(8-ethyl-3 a-nortropanyloxy )-6,1 1-dihydro-dibenzo[b,elthiepine- S-oxide.

5. The compound of claim 1, which is l1-(8-ethyl-3 a-nortropanyloxy )-6,l 1-dihydro-dibenzo[b,e]thiepine- 5,5-dioxide. 

1. A compound of the formula:
 2. The compound of claim 1, which is 6,11-dihydro-11-(3 Alpha -tropanyloxy)dibenzo(b,e)thiepine-5-oxide.
 3. The compound of claim 1, which is 6,11-dihydro-11-(3 Alpha -tropanyloxy)dibenzo(b,e)thiepine-5,5-dioxide.
 4. The compound of claim 1, which is 11-(8-ethyl-3 Alpha -nortropanyloxy)-6,11-dihydro-dibenzo(b,e)thiepine-5-oxide. 